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Event-related potentials in alcoholic fathers and their sons
Alcohol. Vol. 8., pp. 321-327. e PeCgamonPress plc, 1991. Printed in the U.S.A.
0741-8329/91 $3.00 + .00
RAPID COMMUNICATION
Event-Related Potentials in Alcoholic Fathers and Their Sons S T E P H E N C. W H I P P L E , S T E V E N M. B E R M A N I A N D E R N E S T P. N O B L E
Alcohol Research Center, Neuropsychiatric blstitute and the Brain Research Institute Universit 3, o f California, Los Angeles, CA 90024-1759 R e c e i v e d 24 J a n u a r y 1991; A c c e p t e d 26 F e b r u a r y 1991 WHIPPLE. S. C., S. M. BERMAN AND E. P. NOBLE. Event-relatedpotentials in alcoholicfathers and their sons. ALCOHOl 8141 321-327, 1991.--ERPs were recorded during a simple color discrimination and a more difficult visual continuous performance task (CPT) from three father-son (n = 15) pair groups: recovering alcoholics with a family history of alcoholism and their sons (A + I, nonalcoholics with a family history of alcoholism and their sons (NA + ), and nonalcoholics with no family history of alcoholism and their sons ( N A - I. The sons, aged 8 to 12, had not begun drinking or using other drugs. Groups were matched on age, education and socioeconomic status. There were two principal findings. Compared to nonalcoholic groups, both A + sons and fathers exhibited increased latency and decreased amplitude of P3 for the difficult task, but not for the easy task. This result helps to explain previous inconsistencies in the literature, and strengthens the suggestion that one indication of a vulnerability to develop alcoholism is an abnormal P3, when elicited by an appropriate task. Additionally. A + fathers had more negative amplitudes for a late slow wave in both tasks, suggesting electrophysiological consequences of long-term alcohol abuse. Event-related potentials
P3
Familial alcoholism
Vulnerability marker
ELECTROPHYSIOLOG1CAL techniques, especially event-related potentials (ERPs), have been used to assess the CNS functioning of alcoholics in a number of laboratories (8, 16, 19, 25, 29), with special interest focused on the late positive complex (LPC), a large positive deflection occurring at a minimum latency of about 300 ms from stimulus onset. The LPC has been decomposed into various components (30), including a centroparietal P3b which is largest to attended targets of low probability, and an overlapping slow wave (SW) which is of negative polarity at frontal sites but is positive parietally. Most research has focused on the P3b component which is usually referred to as P300 or P3. Despite a considerable body of work [reviewed in (6)], the functional significance of P3 remains controversial, although its sensitivity to instructional manipulations indicates it is related to directed strategies of cognitive processing. Long-term alcoholics have been reported to exhibit increased P3 latency (18), decreased P3 amplitude (8, 16, 24), or both (25), compared to age-matched controls. More recently, evidence has been accumulating which demonstrates both lower amplitude (1, 2, 7, 15, 26, 33) and longer latency P3 (7, 12, 31, 32) in nonalcoholic sons of alcoholics. This finding is important for two reasons. First, it raises the possibility that a portion of the reduced neuroelectric response seen in familial alcoholics (those men with a family history of alcoholism) preceded their heavy drinking. Since approximately 50% of all alcoholics have
a family history of alcoholism (5), the lack of consensus among previous studies regarding which measures of P3 are affected may be due to heterogeneity in the samples studied with respect to this variable. At the inception of this study, only one report has assessed ERPs in alcoholics with a positive family history (FH + ) and a negative family history ( F H - ) of alcoholism (17). It was determined that both FH + and F H - alcoholics had reduced P3s to auditory and visual stimuli, but it was the FH + alcoholics who exhibited the greatest P3 amplitude reductions. Reduced brain electrical activity in nonalcoholic sons of alcoholics is also important because it may be possible to utilize this atypical neuroelectric response as one component of an atypical neurocognitive profile that could serve as a marker for vulnerability to alcoholism (33). As it is well established that alcoholism runs in families (5), it is of interest to note that one of the best predictors for alcoholism is the presence of a close biological alcoholic relative (4,10). Until genetic factors that confer vulnerability to abuse alcohol are specified, it may be possible to identify phenotypes through examination of covarying physiological and behavioral markers. ERP studies undertaken to date, however, have only assessed alcoholics or sons of alcoholics, but not father-son pairs. One of the goals of the present study was to compare electrophysiological functioning in alcoholic fathers and their sons to nonalcoholic fathers and their sons under similar task conditions,
tRequests for reprints should be addressed to Dr. Steven Berman, Neuropsychiatric Institute, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024-1759.
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Although ERP differences between alcoholics and controls have been noted for both exogenous and endogenous components [see (25J for review], ERP differences between sons of alcoholics and nonalcoholics have been seen primarily in reduced amplitude and/or increased latency of the P3 component. However. not all studies assessing high-risk individuals have reported differences. For example, in a series of studies {21-231 o f college students, neither anlplitude nor latency changes were found as a function of family history o f alcoholism. However. as noted in a recent review on the characteristics o f sons of alcoholics. college students are likely to be a self-selecting group with minimal cognitive deficits (201. If the expression of an inherited predisposition to alcoholism involves both electrophysiological and cognitive abnormalities, children of alcoholics who are most at risk may not enjoy sufficient academic success to reach college, and will not be represented in this population. With the exception of one study (21. a c o m m o n factor among the paradigms demonstrating ERP differences between high- and low-risk individuals is the increased processing demands of the tasks used to elicit the ERPs. The studies conducted by Polich and colleagues (21-23) have relied on discrimination tasks where subjects must respond differentially to relatively simple pure tone stimuli. The only study not using college students which failed to find P3 differences associated with fanfily history for alcoholism asked subjects to discriminate tone pitch or select red from green circles (16L Thus brain regions where more complex information processing occurs may not have been engaged. In short, differences may only surface when high-risk subjects are given an increased cognitive challenge, or when specific types of processing are invoked. The second goal of the present study addressed this issue by using two visual tasks: the first, a relatively simple color discrimination task and the second, a more complex continuous performance task requiring increased cognitive processing. METHOD
S,bjects Father-son pairs were selected from three groups. Group A + consisted of recovering alcoholics who also had a family history of alcoholism {n = 15l, and their sons (n = 151. Group NA - was composed o f nonalcoholics ( n = 151 who had an absence o f a family history of alcoholism, and their sons ( n = 151. Group NA + consisted of nonalcoholic men who bad a positive family history' of alcoholism ( n = 151. and their sons ( n = 15). Family history o f alcoholism was defined as the presence of at least one first or second degree alcoholic relative of the father. Selection criteria, determined by interview with mothers and fathers, included 11 at least two years o f sobriety for the recovering alcoholic fathers, 2) no history or current status of drinking problems in the son's mother, and only minimal drinking during the son's gestation, 3) no history or current status o f medical or psychiatric history, 4) no current use of psychoactive medication, 5J no problems with vision or hearing (corrected-to-normal vision was acceptablel, 6) no history o f major head trauma, 7) collateral verification o f the father's past and present drinking habits, treatment history (if any) and medical status, and 81 no history o f alcohol or illicit drug use by the son. Fathers' alcohol dependance was diagnosed according to DSM-III-R criteria (American Psychiatric Association, 1987). Family history of alcoholism was determined by questionnaires sent to family members. The three groups were matched on age, education and socioeconomic status (see Table I). Father-son pairs in each group were tested on different occasions. All subjects gave informed consent before
TABLE I SAMPLE DEIvlOGRAPHICSIMEANS ÷ STANDARD ERROR OF THE MEANJ Group A+ (n= 15~
Age (yearst Education (yearsl
10.1 _+ 0.4 4.9 + 0.4
Age (years) Education (yearsl Annual l n c o m e l x IK~
41.0 = 1.3 15.2 _+ 0.6 45.5 -+ 5.5
Number of Alcoholic Relatives First Degree 2.1 -+ 0.3 Second Degree 2.4 -+. 0.5 Alcohol Use Age First Use Age Problems Began Lifetime Intake (gal abs. EIOHI Years Recovering
14.7 = 0.3 19.2 ~- 1.7 224.5 -+ 34.1/ 4.8 =
NA + (n= 151
NA (n= 151
Soils 10.2 -+. I).4
10.5 ~ 0.4
5.0 -+ 0.5
4.9 ~ 0.3
Fathers 4(I.5 - I.I 17.2 z 0.5 37.3 _~ 4.1
44.7 + 1.6 16.8 --- 0.6 47.5 = 5.7
0.7 ~_ 0.2
0
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16.3 = 1.4
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14.0 _.+ 4.0
31.8 -__ 8.0
0.8
the experiment and were paid for their participation.
ERP Tasks Two tasks were presented to each subject. The first was an easy color discrimination task ( C O L O R L Subjects sat a distance of approximately 125 cm from a video monitor and watched a sequence o f blue and orange triangles, presented one at a time. The triangles subtended a visual area equal to 2°× 3.5 °. At the center of the triangle was a small white box containing the numeral 0. Subjects were instructed to fix their gaze on the 0 during the run and to refrain from making extraneous eye movements. Four runs consisting of 200 stimuli per run were presented to each subject. On each run, one color was designated as the target. The subject was instructed to keep a mental tall,,,, o f the target triangles. Targets o c c u r r e d r a n d o m l y with an average probability of 0.20. Individual sequences of stimuli were randomly generated for each run for each subject. The stimuli were presented for 83.5 ms at random ISis between 1000-1500 ms. Target color was counterbalanced between runs. Trials on which there were excessive eye movements or muscle artifacts ( _+ 100 p-VI were rejected on-line. The second paradigm was a continuous performance task (CPT) which required that subjects monitor a sequence o f colored shapes. The subject's task was to keep a mental tally of the number of stimuli which matched the immediately preceding stimulus on three stimulus dimensions. The relevant stimulus dimensions used were shape: circles, squares, and triangles: color: blue, green, orange, and violet: and the identity o f a numeral. the digits 0 - 9 , located in a white box at the center o f the shape. A total o f 120 stimuli were possible. For exanaple, if a subject saw, on successive trials, a violet square with the number three in the center, he would count that as a match. The triangles used were identical to those used in the color discrimination task and the circle and square were of comparable size. As in the first task, each o f four runs consisted of 200 stimuli. The sequence
ERPS IN ALCOHOLIC FATHERS AND THEIR SONS
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of stimuli were randomly generated, except for two constraints-target probability was 10c/c, and three matching stimuli in a row did not occur. The stimuli were presented for 83.5 ms at a constant ISI of 2000 ms. Trials contaminated by excessive eye movements or other artif.'Lcts { _+ 100 i.tV) were rejected on-line. At the end of each run subjects were asked how many targets they counted and were informed how many had actually been presented.
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Data Acquisition The EEG was recorded from electrodes at Fz, Cz, Pz, OI,and 0 2 according to the International 10-20 System. Linked reference electrodes were placed on the mastoids and an electrode at Fpz served as ground. Eye movements were monitored and recorded with an electrode placed above the right eye and referenced to the linked mastoids. The impedance of all electrodes was kept below 10 kohm throughout the session. The EEG (bandpass of 0.15-25 Hz) was sampled over a 715 ms epoch (rate=350 Hz) for the COLOR task and over a 1000 ms epoch (rate=250 Hz) for the CPT. For both tasks the recording epoch included 50 ms of prestimulus baseline.
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Averages were computed on-line for target and nontarget stimuli of the COLOR task and matching and nonmatching stimuli of the CPT. P3 latencies were determined by visual inspection of the individual averages for each subject's target and nontarget ERPs. at the electrode of maximum amplitude and assessed with 3 x 2 (group z stimulus) repeated measure ANOVA. Peak amplitude was measured at this latency for each electrode, relative to the 50 ms prestimulus baseline. Amplitude of slow wave (SW) was measured as mean amplitude over a latency window subsequent to P3. P3 and SW amplitudes were analyzed using repeated measures ANOVAs with the factors of group ( A + vs. N A + vs. N A - ) . stimulus (target vs. nontarget), and electrode (Fz, Cz. Pz, O t , 02). Because a repeated measures design was used, if was necessary, to correct for possible violations of the homogeneity assumption t13). Therefore, all main effects and interactions involving repeated measure factors were evaluated using reduced degrees of freedom (14). An alpha level of 0.05 was adopted. Tests revealing significant interactions were followed by tests of simple effects using Bonferoni significance levels. Significant main effects were followed by post hoc comparisons. An additional ANOVA directly tested the hypothesis of reduced P3 for the A + group for the stimulus type (targets) and electrode site (Pz) where P3 is maximal. Since there were no observable P3 differences between the NA + and N A groups, the two groups ',,,,ere collapsed for this analysis. Analysis of the behavioral data consisted of four separate one-way ANOVAs testing the effect of group membership for the error rates of each task for sons and fathers. RESULTS
Electrophysiological Data Color discrimination task. Grand mean ERPs for this task averaged across groups of sons and fathers are shown in Fig. 1. Since there were no significant differences between the two occipital sites, only Ol will be presented. Both fathers' and sons" ERPs were characterized by a series of positive and negative deflections, with the sons" peak latencies being somewhat longer than their fathers'. Fathers" and sons' ERPs had similar waveshapes, although an early posterior positivity was much larger in
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FIG. 1. Grand mean COLOR task ERPs for sons (top panel) and fathers (bottom panel) at the Fz. Cz. Pz and O1 electrode sites. Solid lines are larger ERPs and dotted lines are ERPs to nontargets. For this and all subsequent figures, calibration marks on the abscissa equal I00 ms intervals and the calibration mark at stimulus onset equals 2 p.V, positive upwards. the children, as also seen in previous developmental investigations, (3,9). P3 was identified as a large centroparietal positivity peaking at 370 ms in fathers and 440 in sons which was larger to targets than nontargets, as can be seen in Fig. 1. Since the subsequent slow wave had no easily identifiable peak, and may have continued beyond the recording epoch in some subjects, it was measured as the mean amplitude from 485-635 ms in fathers and 535-635 ms in sons. For all components and both tasks in fathers and sons, there were significant effects of electrode site, representing differential amplitudes recorded from the different electrodes. Additionally. all the deflections associated with P3 showed a main effect of stimulus, due to larger amplitudes in target waveforms, and interactions of stimulus and electrode, due to the effect being primarily centroparietal. These findings would be expected in
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any P3 paradigm and will not be discussed in detail. For the COLOR task, there were no significant group effects for the sons in the overall or P3 analyses. The only significant group difference among the fathers was for the SW component, F(2,42)= 5.20, p < . 0 1 . Post hoc analysis showed that the three groups were all significantly different from one another, with the NA + fathers having the most positive amplitudes and the A + fathers having the most negative amplitudes. Continuous pelformance task. While data from all subjects was analyzed on the COLOR task. four A + fathers and three N A - fathers were dropped from the CPT task due to excessive eye movement contamination. As shown in Fig. 2, a late centroparietal positivity that is larger to target stimuli can also be identified, at latencies about 55 ms longer than the late positivity associated with the COLOR task. Presumably, these longer latencies (about 425 ms in fathers and 500 ms in sons) derive from the greater complexity of the CPT task. P3 overlapped with a somewhat more complete SW (due to the longer recording epoch), which was measured as mean area over the latter portion of the waveform. As shown in 'Fig. 2, the ERP waveform exhibits a consistently negative-going course from the P3 peak to the end of the epoch. Because the slow wave measurement window onsets on this downward slope, an early onset will tend to produce more positive values, due to inclusion of more P3, and a later onset will'tend to produce more negative values. For all 6 groups, onset of SW was indicated by separate principal components analyses. Although a SW component was identified for each group, the solutions were dissimilar enough that factor scores could not be analyzed across groups, and therefore will not be further discussed in relation to the baseline-to-peak measurements. SW was terminated at 910 ms, with onset as follows: fathers: A + = 6 1 0 , NA+=625, NA-=685; sons: A + = 7 0 5 , NA+=660, N A - = 635. This would bias the A + fathers (earliest onset) to have more positive slow wave than control groups and A + sons (latest onset) to have more negative slow waves. Despite the use of these measurement windows for CPT slow wave, the slow wave pattern reported above for the COLOR task was replicated. That is, A + fathers evinced more negativity during the SW epoch than either N A + or N A - fathers, F ( 2 , 3 5 ) = 7 . 0 7 , p < 0 . 0 1 , and there was no SW group difference in sons. P3 amplitude was significantly reduced for A + fathers, as compared to NA + and N A - fathers, both across all stimuli and recording sites, F(2,35)= 12.02, p < 0 . 0 0 1 , and for target stimuli at Pz, F ( I , 3 6 ) = 10.31, p < 0 . 0 0 3 . As can be seen in Fig. 3, P3 in A + sons was also of lower amplitude than that recorded in other groups, but the difference was not significant across stimuli and recording sites. However, the A + sons had a significantly smaller target P3 at Pz than the nonalcoholic sons, F( 1,43) = 4.33, p < 0 . 0 5 . A + P3 latency was prolonged across stimuli both for the fathers [ A + = 5 0 6 , NA+=408, NA-=421; F ( 2 , 3 5 ) = 2 3 . 0 2 , p < 0 . 0 0 0 1 ] and sons [ A + = 5 7 1 , N A + = 5 0 5 , N A - = 4 7 0 ; F(2,42)= 14.99, p<0.0001]. For targets only, the effect was also large [ f a t h e r s - - A + = 4 8 7 , NA ( + and - combined) = 426; F( 1,36) = 10.19, p < 0 . 0 0 3 ; sons-- A + = 573, NA = 475; F(1,43) = 23.06, p<0.0001]. It is important to note that the significant differences observed are differences in group means. Because only some of the sons of alcoholics will go on to develop alcoholism themselves, we examined the distribution of P3 amplitudes in an attempt to isolate a subgroup of A + boys whose P3 amplitude is widely discrepant from control values. To this end, the tenth percentile of the N A - boys P3 amplitude scores was established as a criterion, and it was determined that seven out of the fifteen A + boys had amplitudes lower than this value. Two of the seven fathers of boys in this subgroup had P3 amplitudes less
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FIG. 2. Grand mean CPT ERPs for sons (top panel) and fathers (bottom panel) at the Fz, Cz, Pz and O1 electrode sites. Solid lines are ERPs to matching (target) stimuli and dotted lines are ERPS to nonmatches (nontargets). Calibration marks on the abscissa equal 100 ms intervals and the calibration mark at stimulus onset equals 2 ~V, positive upwards.
than the lowest N A - fathers. Two other fathers' data were not analyzed due to excessive eye movements, and the three other fathers of these boys had a mean percentile rank of 34. Thus, although this sample is too small to draw firm conclusions, there may be a correspondence between extremely low amplitude P3s in A + sons and their fathers.
Behavioral Data As expected, error rates were lower on the COLOR task than the CPT. For the sons the mean error rates (and standard deviations) for the COLOR task were: A + , 3.9% (I.9); N A + , 4.2% (3.6); N A - , 3.8% (3.1). For the fathers the means were: A + , 0.9% (1.4); N A + , 2.2% (1.8); N A - , 0.8% (1.2). For the CPT the mean error rates for the sons were: A + , 15.5% (7.2); N A + , 9.9% (5.7); N A - , 12.3% (4.8). For the fathers, the mean error
ERPS IN ALCOHOLIC FATHERS AND THEIR SONS
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rates for the CPT were: A + , 9.8% (2.5); N A + , 10.9% (4.2); N A - , 10.6% (2.3). Group effects did not reach significance for either task. DISCUSSION
In this study, 8-12-year-old sons of familial alcoholics were found to have reduced amplitude and prolonged latency P3 elicited during a moderately demanding visual discrimination task, even though these boys had not yet begun to drink alcohol or use other drugs. About half of these boys had P3 amplitudes which were extremely low as compared to sons of nonalcoholics, i.e., less than the tenth percentile. For the same task. the boys' recovering alcoholic fathers also exhibited these effects. These findings add to previous reports of P3 deficits in alcoholic men and their sons. However, as seen in Fig. 3, no P3 differences were noted between alcofiolics and nonalcoholics when the eliciting task was a simple color discrimination for either father or son groups. This supports our contention that the conflicting results in the literature may derive partially from task differences. Studies which failed to observe significant differences between sons of alcoholics and nonalcoholics (16, 21-23) employed relatively simple sensory discriminations. On the other hand, the CPT task of the present study and the mental rotation task of Begleiter and associates (1) and O ' C o n n o r and associates (15) demanded considerably more processing of each stimulus. In the current context, the CPT demanded processing of three stimulus dimensions, a relative rather than an absolute target criterion, and successive matching to sample operations. In contrast to the P3 decrement, which highlights the effect of the eliciting task, both tasks produced a more negative SW component associated with the alcoholic men, but not their sons. This finding is consistent with Grant's (11) hypothesis that longterm alcohol abuse may result in a subacute "intermediate duration organic mental disorder." However, the cuo'ent data, from alcoholics abstinent for an average of 4.8 years, cannot determine whether the SW. change is reversible after longer abstinence. Moreover, while the most plausible explanation for the SW findings involves chronic alcohol abuse, our data cannot choose between an explanation in terms of alcohol abuse alone, or in its interaction with a particular genotype. The lack of SW findings in the A + sons indicates that the genetic contribution
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presumed to produce the P3 changes reported herein is not sufficient to produce SW changes. However, a genotype conferring a high risk for alcohol-abuse may or may not be necessary for expression of those SW changes. A reduction in amplitude of any ERP component can come about in several ways. It is generally assumed that a reduced amplitude in a component results from a reduction in the neural activity which contributes to that component. This can arise for P3 in at least two ways. First, if the target is perceived as such but the neural output is deficient• Alternatively, a reduction in P3 amplitude may arise if the event is not perceived as the target, i.e., if it is " m i s s e d " in the signal detection sense. On the other hand, the amplitude of P3 elicited on single trials may be robust and vary little from trial to trial. However, there may be a significant variation in the time locking of the component to stimulus onset, i.e, in its peak latency. In this instance, a broader but lower amplitude waveform is produced. Finally, a lower amplitude component can also result from the superposition of another component of opposite polarity in the latency range of the component of interest. In the present study it is difficult to ascertain the exact reason for the lower P3 amplitudes of alcoholic fathers and their sons. Since all subjects were given practice on the CPT until they correctly identified five consecutive matches, it is unlikely that they were misperceiving the target stimuli. In addition, there was not a significant difference in the error rates between the A + and N A - boys: Since single trials were not recorded (averages were computed on-line), it is not possible to rule out latency jitter as a cause of the reduced amplitude P3. However, trial-to-trial variability in responding to target stimuli may also be significant for understanding the nature of the atypical P3s of A + fathers and their sons. This is an empirical question awaiting further study. Visual inspection of the grand mean waveforms from the CPT targets (Fig. 3) shows that the difference between A + and control groups may not be restricted to P3. Particularly for the sons, the maximal difference appears in a negativity between the P2 and P3 peaks. This suggests that a type of processing needed for certain demanding tasks may result in scalp-recorded negativity that is larger for alcoholics and their sons, and that this negativity coincides more with the peak of P3 in adults, where P3 peaks at shorter latency. Inspection of the grand mean waveforms from the CPT (Fig. 2) may provide an additional clue to the underlying functional difference between groups. Note that the waveform for the target stimuli (solid line) at the Pz and Cz electrode locations for the A + boys is quite similar to the nontarget waveform (dotted line). A similar pattern is seen in the fathers. This would seem to indicate that the A + boys and their fathers are responding in a similar fashion to both classes of stimuli, whereas the other subjects were not. Even though the interaction between group and stimulus was not significant, there was a trend in the interaction for the sons P3 data ( p = 0 . 1 0 ) . Projesz and associates (25,27) report similar findings in alcoholic subjects, i.e., similar responses to both target and nontarget stimuli. Alcoholics and their sons may have difficulty differentiating between targets and nontargets in the use of some processing mechanism. The nonalcoholic controls who had a family history of alcoholism were included in the present study because nonalcoholic family history positive men have been shown to have reduced neuropsychological performance (28). We hypothesized that if familial alcoholism has a genetic component and P3 amplitude. reductions are one phenotypic manifestation, then perhaps some of these men and their sons would exhibit the same phenotype as the alcoholics, producing a group lying somewhere between the other two groups. Comparisons between NA + fathers and sons and N A - fathers and sons revealed no significant differ-
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e n c e s in either amplitude or latency o f P3 on either the C O L O R task or C P T . A l t h o u g h there were small S W differences between N A + and N A fathers, they went in opposite directions for the two tasks. While Fig. 3 s h o w s the C P T task did produce LPC amplitudes intermediate between the N A - and A + m e n , the differences between N A + and N A - were not significant. Because the N A + subjects are, on the average, less closely related to the alcoholic m e m b e r s of their families than the A + subjects, the N A + group is likely to include more subjects that did not inherit the g e n e s that put them at risk for alcoholism. Therefore. any physiological c o n s e q u e n c e s o f these g e n e s will be more difficult to d e m o n s t r a t e in the NA + group. T h e results o f this study support the hypothesis that P3 abnormalities can be used as one c o m p o n e n t of an atypical neurocognitive profile which can serve as a vulnerability m a r k e r for alcoholism, but only if a sufficient d e m a n d i n g and appropriate task is e m p l o y e d . Further research is needed to delineate the m i n i m u m requirements o f an appropriate task. However, it is important to assess the P3 variable in c o m b i n a t i o n with other m e a s u r e s for the s a m e reason that any single test of a neuropsychological batte~" has little diagnostic significance in isolation:
the defect can be produced by multiple etiologies. While a genetic vulnerability to alcoholism m a y be sufficient to produce reduced P3, it is clearly not a necessary condition, as P3 anaplitude can be reduced by physical factors such as the thickness of the skull, psychological factors such as the motivation of the subject, or by multiple chronic or acute disease states, such as schizophrenia or depression. W e are presently m a k i n g annual evaluations o f the boys of the present study in order to assess the onset and d e v e l o p m e n t o f drinking, drug use and other problem behaviors. In this way we hope to clarify the relative importance of lowered P3 amplitude, and the other c o m p o n e n t s o f the atypical neurocognitive profile reported in our earlier paper (33) as predictive m e a s u r e s with utility lbr early detection and c o u n s e l i n g in children at risk for d e v e l o p i n g alcoholism.
ACKNOWLEDGEMENTS The authors gratefully acknowledge the dedicated participation of the subject volunteers in the present stud.',,. This research was supported by the Seaver Institute. NIAAA grant AA-06960 and AA-08020, and the Pike Professorship of Alcohol Studies.
REFERENCES I. Begleiter, H.: Porjesz, B.: Bihari. B.; Kissin, B. Event-related brain potentials in boys at risk for alcoholism. Science 225:1493-1496; 1984. 2. Begleiter. H.; Porjesz. B.; Rawlings. R: Eckardt. M. Auditor2,., recover3.' functions and P3 in boys at high risk for alcoholism. Alcohol 4:315-321: 1987. 3. Berman. S.: Friedman. D.: Cramer. M. A developmental stud), of event-related potentials to pictures and words during direct and indirect memory, Int. J. Psychophysiol.. in press: 1990. 4. Cloninger, C. R.; Bohman, M.: Sigvardsson. S. Inheritance of alcohol abuse. Arch. Gen. Psychiatry 38:861-868: 1981, 5. Cotton, N. S. The familial incidence of alcoholism. J. Stud. Alcohol 40:89-116: 1979. 6. Donchin, E.; Coles, M. G. H. Is the P300 component a manifestation of context updating'? Behav. Brain Sci. 11(3):357-374; 1988. 7. Elmasian, R.; Neville, H.; Woods. D.: Schuckit, M.; Bloom. F. Event-related brain potentials are different in individuals at high and low risk for developing alcoholism. Proc. Natl. Acad. Sci. USA 79:7900-7903; 1982. 8. Emmerson, R. Y.; Dustman, R. E.: Shearer, D. E.; Chamberlin. H. M. EEG. visually evoked and event related potentials in young abstinent alcoholics. Alcohol 4:241-248: 1987. 9. Friedman, D., Sutton, S., Pumum, L.. Brown. C., Jr.; ErlenmeyerKimling, L. ERP components in picture matching in children and adults. Psychophysiology 25:570-590: 1988. 10. Goodwin, D. W.; Schulsinger, F.: Moiler. N.; Hermansen, L.; Winokur, G.: Guze. S. B. Drinking problems in adopted and nonadopted sons of alcoholics. Arch. Gen. Psychiatry 31:164-169; 1974. 11. Grant, I. Intermediate-duration (subacute) organic mental disorder of alcoholism. In: Grant, I., ed. Neuropsychiatric correlates of alcoholism. Washington, DC: American Psychiatric Press; 1986:38-60. 12. Hill, S. Y.; Steinhauer. S. R.: Zubin, J.; Baughman, T. Event-related potentials as markers for alcoholism risk in high density families. Alcoholism Clin. Exp. Res. 12:545-554; 1988. 13..lennings, J. R. Editorial policy on analyses of variance with repeated measures. Psychophysiology 24:474--475; 1987. 14. Jennings, J. R.; Wood, C. C. The e-adjustment procedure for repeated-measures analyses of variance. Psychophysiology 13:277278; 1976. 15. O'Connor. S.; Hesselbrock, V.: Tasman, A.; DePalma, N. P3 amplitudes in two distinct tasks are decreased in young men with a history of paternal alcoholism. Alcohol 4:323-330; 1987. 16. Parsons, O. A.; Sinha, R.; Williams, H. L. Relationships between neuropsychological test performance and event-related potentials in
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alcoholic and nonalcoholic samples. Alcohol.: Clin. Exp. Res. 14(5): 746-755; 1990. Patterson, B. W.: Williams. H. L.: McLean. G. A.; Smith. L. T.; Schaeffer. K. W. Alcoholism and family history, of alcoholism: El: fects on visual and audito R, event-related potentials. Alcohol 4:265274: 1987. Pfefferbaum, A.; Horvath, T. B.: Roth. W. T.: Kopell. B. S. Event-related potential changes in chronic alcoholics. Electroencephalogr. Clin. Neurophysiol. 47:637-647; 1979. Pfefferbaum. A.; Horvath, T. B.: Roth. W. T.; Clifford, S. T.: Kopell, B. S. Acute and chronic effects of ethanol on event-related potentials. In: Begleiter. H.. ed. Biological effects of alcohol. New York: Plenum Press; 1980:625-639. (Adv. Med. Exp. Biol.. vol. 126.~ Pihl, R. O.: Peterson, J.; Finn, P. Inherited predisposition to alcoholism: characteristics of sons of male alcoholics. J. Abnoml. Psychol. 99(3):291-301; 1990. Polich, J.; Bloom, F. E. P300 from normals and adult children of alcoholics. Alcohol 4:301-305; 1987. Polich. J.; Bloom. F. E. Evem-related brain potentials in individuals at high and low risk for developing alcoholism: failure to replicate. Alcohol.: Clin. Exp. Res. 12:368-373: 1988, Polich. J.; Bums. T.; Bloom, F. E. P300 and the risk for alcoholism: family history, task difficulty, and gender. Alcohol.: Clin. Exp. Res. 12:248-254; 1988. Porjesz, B.; Begleiter. H. Human evoked brain potentials in alcoholics. Alcoholism 5:304-317; 1981. Porjesz, B.; Begleiter, H. Human brain electrophysiology and alcoholism. In: Tarter, R.; Van Thiel, D.. eds. Alcohol and the brain: chronic effects. New York: Plenum; 1985:139-182. Porjesz, B.: Begleiter, H. Event-related potentials in individuals at risk for alcoholism. Alcohol 5:465--469; 1990. Porjesz, B.; Begleiter, H.; Bihari, B.; Kissin. B. The N2 component of the event-related brain potential in abstinent alcoholics. Electroencephalogr. Clin. Neurophysiol. 66:121-131 : 1987. Schaeffer, K. W.; Parsons, O. A.; Yohman, J. R. Neuropsychological differences between male familial and non-familial alcoholics and nonalcoholics. Alcoholism 8:347-351: 1984. Shagass. C. Alcohol and human evoked potentials. Paper presented at VII World Congress of Psychiatry, Vienna, Austria, July; 1983. Squires, N. K.; Squires, K. C.; Hillyard, S. A. Two varieties of long-latency positive waves evoked by unpredictable auditory stimuli in man. Electroencephalogr. Clin. Neurophysiol. 38:387-401; 1975. Steinhauer, S. R.; Hill, S. Y.; Zubin, J. Event-related potentials in
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alcoholics and their first-degree relatives. Alcohol 4:307-314; 1987. 32. Whipple. S. C.: Noble. E. P. The effect of familial alcoholism on visual event-related potentials. Psychophysiology 23:470: 1986.
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33, Whipple. S. C,: Parker. E. S,; Noble, E. P. An atypical neurocognitive profile in alcoholic fathers and their sons. J. Stud. Alcohol 49:240-2'44; 1988.
0741-8329/91 $3.00 + .00
RAPID COMMUNICATION
Event-Related Potentials in Alcoholic Fathers and Their Sons S T E P H E N C. W H I P P L E , S T E V E N M. B E R M A N I A N D E R N E S T P. N O B L E
Alcohol Research Center, Neuropsychiatric blstitute and the Brain Research Institute Universit 3, o f California, Los Angeles, CA 90024-1759 R e c e i v e d 24 J a n u a r y 1991; A c c e p t e d 26 F e b r u a r y 1991 WHIPPLE. S. C., S. M. BERMAN AND E. P. NOBLE. Event-relatedpotentials in alcoholicfathers and their sons. ALCOHOl 8141 321-327, 1991.--ERPs were recorded during a simple color discrimination and a more difficult visual continuous performance task (CPT) from three father-son (n = 15) pair groups: recovering alcoholics with a family history of alcoholism and their sons (A + I, nonalcoholics with a family history of alcoholism and their sons (NA + ), and nonalcoholics with no family history of alcoholism and their sons ( N A - I. The sons, aged 8 to 12, had not begun drinking or using other drugs. Groups were matched on age, education and socioeconomic status. There were two principal findings. Compared to nonalcoholic groups, both A + sons and fathers exhibited increased latency and decreased amplitude of P3 for the difficult task, but not for the easy task. This result helps to explain previous inconsistencies in the literature, and strengthens the suggestion that one indication of a vulnerability to develop alcoholism is an abnormal P3, when elicited by an appropriate task. Additionally. A + fathers had more negative amplitudes for a late slow wave in both tasks, suggesting electrophysiological consequences of long-term alcohol abuse. Event-related potentials
P3
Familial alcoholism
Vulnerability marker
ELECTROPHYSIOLOG1CAL techniques, especially event-related potentials (ERPs), have been used to assess the CNS functioning of alcoholics in a number of laboratories (8, 16, 19, 25, 29), with special interest focused on the late positive complex (LPC), a large positive deflection occurring at a minimum latency of about 300 ms from stimulus onset. The LPC has been decomposed into various components (30), including a centroparietal P3b which is largest to attended targets of low probability, and an overlapping slow wave (SW) which is of negative polarity at frontal sites but is positive parietally. Most research has focused on the P3b component which is usually referred to as P300 or P3. Despite a considerable body of work [reviewed in (6)], the functional significance of P3 remains controversial, although its sensitivity to instructional manipulations indicates it is related to directed strategies of cognitive processing. Long-term alcoholics have been reported to exhibit increased P3 latency (18), decreased P3 amplitude (8, 16, 24), or both (25), compared to age-matched controls. More recently, evidence has been accumulating which demonstrates both lower amplitude (1, 2, 7, 15, 26, 33) and longer latency P3 (7, 12, 31, 32) in nonalcoholic sons of alcoholics. This finding is important for two reasons. First, it raises the possibility that a portion of the reduced neuroelectric response seen in familial alcoholics (those men with a family history of alcoholism) preceded their heavy drinking. Since approximately 50% of all alcoholics have
a family history of alcoholism (5), the lack of consensus among previous studies regarding which measures of P3 are affected may be due to heterogeneity in the samples studied with respect to this variable. At the inception of this study, only one report has assessed ERPs in alcoholics with a positive family history (FH + ) and a negative family history ( F H - ) of alcoholism (17). It was determined that both FH + and F H - alcoholics had reduced P3s to auditory and visual stimuli, but it was the FH + alcoholics who exhibited the greatest P3 amplitude reductions. Reduced brain electrical activity in nonalcoholic sons of alcoholics is also important because it may be possible to utilize this atypical neuroelectric response as one component of an atypical neurocognitive profile that could serve as a marker for vulnerability to alcoholism (33). As it is well established that alcoholism runs in families (5), it is of interest to note that one of the best predictors for alcoholism is the presence of a close biological alcoholic relative (4,10). Until genetic factors that confer vulnerability to abuse alcohol are specified, it may be possible to identify phenotypes through examination of covarying physiological and behavioral markers. ERP studies undertaken to date, however, have only assessed alcoholics or sons of alcoholics, but not father-son pairs. One of the goals of the present study was to compare electrophysiological functioning in alcoholic fathers and their sons to nonalcoholic fathers and their sons under similar task conditions,
tRequests for reprints should be addressed to Dr. Steven Berman, Neuropsychiatric Institute, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024-1759.
321
322
WHIPPLE. B E R M A N A N D N O B L E
Although ERP differences between alcoholics and controls have been noted for both exogenous and endogenous components [see (25J for review], ERP differences between sons of alcoholics and nonalcoholics have been seen primarily in reduced amplitude and/or increased latency of the P3 component. However. not all studies assessing high-risk individuals have reported differences. For example, in a series of studies {21-231 o f college students, neither anlplitude nor latency changes were found as a function of family history o f alcoholism. However. as noted in a recent review on the characteristics o f sons of alcoholics. college students are likely to be a self-selecting group with minimal cognitive deficits (201. If the expression of an inherited predisposition to alcoholism involves both electrophysiological and cognitive abnormalities, children of alcoholics who are most at risk may not enjoy sufficient academic success to reach college, and will not be represented in this population. With the exception of one study (21. a c o m m o n factor among the paradigms demonstrating ERP differences between high- and low-risk individuals is the increased processing demands of the tasks used to elicit the ERPs. The studies conducted by Polich and colleagues (21-23) have relied on discrimination tasks where subjects must respond differentially to relatively simple pure tone stimuli. The only study not using college students which failed to find P3 differences associated with fanfily history for alcoholism asked subjects to discriminate tone pitch or select red from green circles (16L Thus brain regions where more complex information processing occurs may not have been engaged. In short, differences may only surface when high-risk subjects are given an increased cognitive challenge, or when specific types of processing are invoked. The second goal of the present study addressed this issue by using two visual tasks: the first, a relatively simple color discrimination task and the second, a more complex continuous performance task requiring increased cognitive processing. METHOD
S,bjects Father-son pairs were selected from three groups. Group A + consisted of recovering alcoholics who also had a family history of alcoholism {n = 15l, and their sons (n = 151. Group NA - was composed o f nonalcoholics ( n = 151 who had an absence o f a family history of alcoholism, and their sons ( n = 151. Group NA + consisted of nonalcoholic men who bad a positive family history' of alcoholism ( n = 151. and their sons ( n = 15). Family history o f alcoholism was defined as the presence of at least one first or second degree alcoholic relative of the father. Selection criteria, determined by interview with mothers and fathers, included 11 at least two years o f sobriety for the recovering alcoholic fathers, 2) no history or current status of drinking problems in the son's mother, and only minimal drinking during the son's gestation, 3) no history or current status o f medical or psychiatric history, 4) no current use of psychoactive medication, 5J no problems with vision or hearing (corrected-to-normal vision was acceptablel, 6) no history o f major head trauma, 7) collateral verification o f the father's past and present drinking habits, treatment history (if any) and medical status, and 81 no history o f alcohol or illicit drug use by the son. Fathers' alcohol dependance was diagnosed according to DSM-III-R criteria (American Psychiatric Association, 1987). Family history of alcoholism was determined by questionnaires sent to family members. The three groups were matched on age, education and socioeconomic status (see Table I). Father-son pairs in each group were tested on different occasions. All subjects gave informed consent before
TABLE I SAMPLE DEIvlOGRAPHICSIMEANS ÷ STANDARD ERROR OF THE MEANJ Group A+ (n= 15~
Age (yearst Education (yearsl
10.1 _+ 0.4 4.9 + 0.4
Age (years) Education (yearsl Annual l n c o m e l x IK~
41.0 = 1.3 15.2 _+ 0.6 45.5 -+ 5.5
Number of Alcoholic Relatives First Degree 2.1 -+ 0.3 Second Degree 2.4 -+. 0.5 Alcohol Use Age First Use Age Problems Began Lifetime Intake (gal abs. EIOHI Years Recovering
14.7 = 0.3 19.2 ~- 1.7 224.5 -+ 34.1/ 4.8 =
NA + (n= 151
NA (n= 151
Soils 10.2 -+. I).4
10.5 ~ 0.4
5.0 -+ 0.5
4.9 ~ 0.3
Fathers 4(I.5 - I.I 17.2 z 0.5 37.3 _~ 4.1
44.7 + 1.6 16.8 --- 0.6 47.5 = 5.7
0.7 ~_ 0.2
0
1.2 -+ 0.3
(}
16.3 = 1.4
15.3 __+ 1.3
14.0 _.+ 4.0
31.8 -__ 8.0
0.8
the experiment and were paid for their participation.
ERP Tasks Two tasks were presented to each subject. The first was an easy color discrimination task ( C O L O R L Subjects sat a distance of approximately 125 cm from a video monitor and watched a sequence o f blue and orange triangles, presented one at a time. The triangles subtended a visual area equal to 2°× 3.5 °. At the center of the triangle was a small white box containing the numeral 0. Subjects were instructed to fix their gaze on the 0 during the run and to refrain from making extraneous eye movements. Four runs consisting of 200 stimuli per run were presented to each subject. On each run, one color was designated as the target. The subject was instructed to keep a mental tall,,,, o f the target triangles. Targets o c c u r r e d r a n d o m l y with an average probability of 0.20. Individual sequences of stimuli were randomly generated for each run for each subject. The stimuli were presented for 83.5 ms at random ISis between 1000-1500 ms. Target color was counterbalanced between runs. Trials on which there were excessive eye movements or muscle artifacts ( _+ 100 p-VI were rejected on-line. The second paradigm was a continuous performance task (CPT) which required that subjects monitor a sequence o f colored shapes. The subject's task was to keep a mental tally of the number of stimuli which matched the immediately preceding stimulus on three stimulus dimensions. The relevant stimulus dimensions used were shape: circles, squares, and triangles: color: blue, green, orange, and violet: and the identity o f a numeral. the digits 0 - 9 , located in a white box at the center o f the shape. A total o f 120 stimuli were possible. For exanaple, if a subject saw, on successive trials, a violet square with the number three in the center, he would count that as a match. The triangles used were identical to those used in the color discrimination task and the circle and square were of comparable size. As in the first task, each o f four runs consisted of 200 stimuli. The sequence
ERPS IN ALCOHOLIC FATHERS AND THEIR SONS
323
of stimuli were randomly generated, except for two constraints-target probability was 10c/c, and three matching stimuli in a row did not occur. The stimuli were presented for 83.5 ms at a constant ISI of 2000 ms. Trials contaminated by excessive eye movements or other artif.'Lcts { _+ 100 i.tV) were rejected on-line. At the end of each run subjects were asked how many targets they counted and were informed how many had actually been presented.
SONS NA+
A÷
NA-
Data Acquisition The EEG was recorded from electrodes at Fz, Cz, Pz, OI,and 0 2 according to the International 10-20 System. Linked reference electrodes were placed on the mastoids and an electrode at Fpz served as ground. Eye movements were monitored and recorded with an electrode placed above the right eye and referenced to the linked mastoids. The impedance of all electrodes was kept below 10 kohm throughout the session. The EEG (bandpass of 0.15-25 Hz) was sampled over a 715 ms epoch (rate=350 Hz) for the COLOR task and over a 1000 ms epoch (rate=250 Hz) for the CPT. For both tasks the recording epoch included 50 ms of prestimulus baseline.
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Averages were computed on-line for target and nontarget stimuli of the COLOR task and matching and nonmatching stimuli of the CPT. P3 latencies were determined by visual inspection of the individual averages for each subject's target and nontarget ERPs. at the electrode of maximum amplitude and assessed with 3 x 2 (group z stimulus) repeated measure ANOVA. Peak amplitude was measured at this latency for each electrode, relative to the 50 ms prestimulus baseline. Amplitude of slow wave (SW) was measured as mean amplitude over a latency window subsequent to P3. P3 and SW amplitudes were analyzed using repeated measures ANOVAs with the factors of group ( A + vs. N A + vs. N A - ) . stimulus (target vs. nontarget), and electrode (Fz, Cz. Pz, O t , 02). Because a repeated measures design was used, if was necessary, to correct for possible violations of the homogeneity assumption t13). Therefore, all main effects and interactions involving repeated measure factors were evaluated using reduced degrees of freedom (14). An alpha level of 0.05 was adopted. Tests revealing significant interactions were followed by tests of simple effects using Bonferoni significance levels. Significant main effects were followed by post hoc comparisons. An additional ANOVA directly tested the hypothesis of reduced P3 for the A + group for the stimulus type (targets) and electrode site (Pz) where P3 is maximal. Since there were no observable P3 differences between the NA + and N A groups, the two groups ',,,,ere collapsed for this analysis. Analysis of the behavioral data consisted of four separate one-way ANOVAs testing the effect of group membership for the error rates of each task for sons and fathers. RESULTS
Electrophysiological Data Color discrimination task. Grand mean ERPs for this task averaged across groups of sons and fathers are shown in Fig. 1. Since there were no significant differences between the two occipital sites, only Ol will be presented. Both fathers' and sons" ERPs were characterized by a series of positive and negative deflections, with the sons" peak latencies being somewhat longer than their fathers'. Fathers" and sons' ERPs had similar waveshapes, although an early posterior positivity was much larger in
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FIG. 1. Grand mean COLOR task ERPs for sons (top panel) and fathers (bottom panel) at the Fz. Cz. Pz and O1 electrode sites. Solid lines are larger ERPs and dotted lines are ERPs to nontargets. For this and all subsequent figures, calibration marks on the abscissa equal I00 ms intervals and the calibration mark at stimulus onset equals 2 p.V, positive upwards. the children, as also seen in previous developmental investigations, (3,9). P3 was identified as a large centroparietal positivity peaking at 370 ms in fathers and 440 in sons which was larger to targets than nontargets, as can be seen in Fig. 1. Since the subsequent slow wave had no easily identifiable peak, and may have continued beyond the recording epoch in some subjects, it was measured as the mean amplitude from 485-635 ms in fathers and 535-635 ms in sons. For all components and both tasks in fathers and sons, there were significant effects of electrode site, representing differential amplitudes recorded from the different electrodes. Additionally. all the deflections associated with P3 showed a main effect of stimulus, due to larger amplitudes in target waveforms, and interactions of stimulus and electrode, due to the effect being primarily centroparietal. These findings would be expected in
324
any P3 paradigm and will not be discussed in detail. For the COLOR task, there were no significant group effects for the sons in the overall or P3 analyses. The only significant group difference among the fathers was for the SW component, F(2,42)= 5.20, p < . 0 1 . Post hoc analysis showed that the three groups were all significantly different from one another, with the NA + fathers having the most positive amplitudes and the A + fathers having the most negative amplitudes. Continuous pelformance task. While data from all subjects was analyzed on the COLOR task. four A + fathers and three N A - fathers were dropped from the CPT task due to excessive eye movement contamination. As shown in Fig. 2, a late centroparietal positivity that is larger to target stimuli can also be identified, at latencies about 55 ms longer than the late positivity associated with the COLOR task. Presumably, these longer latencies (about 425 ms in fathers and 500 ms in sons) derive from the greater complexity of the CPT task. P3 overlapped with a somewhat more complete SW (due to the longer recording epoch), which was measured as mean area over the latter portion of the waveform. As shown in 'Fig. 2, the ERP waveform exhibits a consistently negative-going course from the P3 peak to the end of the epoch. Because the slow wave measurement window onsets on this downward slope, an early onset will tend to produce more positive values, due to inclusion of more P3, and a later onset will'tend to produce more negative values. For all 6 groups, onset of SW was indicated by separate principal components analyses. Although a SW component was identified for each group, the solutions were dissimilar enough that factor scores could not be analyzed across groups, and therefore will not be further discussed in relation to the baseline-to-peak measurements. SW was terminated at 910 ms, with onset as follows: fathers: A + = 6 1 0 , NA+=625, NA-=685; sons: A + = 7 0 5 , NA+=660, N A - = 635. This would bias the A + fathers (earliest onset) to have more positive slow wave than control groups and A + sons (latest onset) to have more negative slow waves. Despite the use of these measurement windows for CPT slow wave, the slow wave pattern reported above for the COLOR task was replicated. That is, A + fathers evinced more negativity during the SW epoch than either N A + or N A - fathers, F ( 2 , 3 5 ) = 7 . 0 7 , p < 0 . 0 1 , and there was no SW group difference in sons. P3 amplitude was significantly reduced for A + fathers, as compared to NA + and N A - fathers, both across all stimuli and recording sites, F(2,35)= 12.02, p < 0 . 0 0 1 , and for target stimuli at Pz, F ( I , 3 6 ) = 10.31, p < 0 . 0 0 3 . As can be seen in Fig. 3, P3 in A + sons was also of lower amplitude than that recorded in other groups, but the difference was not significant across stimuli and recording sites. However, the A + sons had a significantly smaller target P3 at Pz than the nonalcoholic sons, F( 1,43) = 4.33, p < 0 . 0 5 . A + P3 latency was prolonged across stimuli both for the fathers [ A + = 5 0 6 , NA+=408, NA-=421; F ( 2 , 3 5 ) = 2 3 . 0 2 , p < 0 . 0 0 0 1 ] and sons [ A + = 5 7 1 , N A + = 5 0 5 , N A - = 4 7 0 ; F(2,42)= 14.99, p<0.0001]. For targets only, the effect was also large [ f a t h e r s - - A + = 4 8 7 , NA ( + and - combined) = 426; F( 1,36) = 10.19, p < 0 . 0 0 3 ; sons-- A + = 573, NA = 475; F(1,43) = 23.06, p<0.0001]. It is important to note that the significant differences observed are differences in group means. Because only some of the sons of alcoholics will go on to develop alcoholism themselves, we examined the distribution of P3 amplitudes in an attempt to isolate a subgroup of A + boys whose P3 amplitude is widely discrepant from control values. To this end, the tenth percentile of the N A - boys P3 amplitude scores was established as a criterion, and it was determined that seven out of the fifteen A + boys had amplitudes lower than this value. Two of the seven fathers of boys in this subgroup had P3 amplitudes less
WHIPPLE, BERMAN AND NOBLE
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than the lowest N A - fathers. Two other fathers' data were not analyzed due to excessive eye movements, and the three other fathers of these boys had a mean percentile rank of 34. Thus, although this sample is too small to draw firm conclusions, there may be a correspondence between extremely low amplitude P3s in A + sons and their fathers.
Behavioral Data As expected, error rates were lower on the COLOR task than the CPT. For the sons the mean error rates (and standard deviations) for the COLOR task were: A + , 3.9% (I.9); N A + , 4.2% (3.6); N A - , 3.8% (3.1). For the fathers the means were: A + , 0.9% (1.4); N A + , 2.2% (1.8); N A - , 0.8% (1.2). For the CPT the mean error rates for the sons were: A + , 15.5% (7.2); N A + , 9.9% (5.7); N A - , 12.3% (4.8). For the fathers, the mean error
ERPS IN ALCOHOLIC FATHERS AND THEIR SONS
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rates for the CPT were: A + , 9.8% (2.5); N A + , 10.9% (4.2); N A - , 10.6% (2.3). Group effects did not reach significance for either task. DISCUSSION
In this study, 8-12-year-old sons of familial alcoholics were found to have reduced amplitude and prolonged latency P3 elicited during a moderately demanding visual discrimination task, even though these boys had not yet begun to drink alcohol or use other drugs. About half of these boys had P3 amplitudes which were extremely low as compared to sons of nonalcoholics, i.e., less than the tenth percentile. For the same task. the boys' recovering alcoholic fathers also exhibited these effects. These findings add to previous reports of P3 deficits in alcoholic men and their sons. However, as seen in Fig. 3, no P3 differences were noted between alcofiolics and nonalcoholics when the eliciting task was a simple color discrimination for either father or son groups. This supports our contention that the conflicting results in the literature may derive partially from task differences. Studies which failed to observe significant differences between sons of alcoholics and nonalcoholics (16, 21-23) employed relatively simple sensory discriminations. On the other hand, the CPT task of the present study and the mental rotation task of Begleiter and associates (1) and O ' C o n n o r and associates (15) demanded considerably more processing of each stimulus. In the current context, the CPT demanded processing of three stimulus dimensions, a relative rather than an absolute target criterion, and successive matching to sample operations. In contrast to the P3 decrement, which highlights the effect of the eliciting task, both tasks produced a more negative SW component associated with the alcoholic men, but not their sons. This finding is consistent with Grant's (11) hypothesis that longterm alcohol abuse may result in a subacute "intermediate duration organic mental disorder." However, the cuo'ent data, from alcoholics abstinent for an average of 4.8 years, cannot determine whether the SW. change is reversible after longer abstinence. Moreover, while the most plausible explanation for the SW findings involves chronic alcohol abuse, our data cannot choose between an explanation in terms of alcohol abuse alone, or in its interaction with a particular genotype. The lack of SW findings in the A + sons indicates that the genetic contribution
325
presumed to produce the P3 changes reported herein is not sufficient to produce SW changes. However, a genotype conferring a high risk for alcohol-abuse may or may not be necessary for expression of those SW changes. A reduction in amplitude of any ERP component can come about in several ways. It is generally assumed that a reduced amplitude in a component results from a reduction in the neural activity which contributes to that component. This can arise for P3 in at least two ways. First, if the target is perceived as such but the neural output is deficient• Alternatively, a reduction in P3 amplitude may arise if the event is not perceived as the target, i.e., if it is " m i s s e d " in the signal detection sense. On the other hand, the amplitude of P3 elicited on single trials may be robust and vary little from trial to trial. However, there may be a significant variation in the time locking of the component to stimulus onset, i.e, in its peak latency. In this instance, a broader but lower amplitude waveform is produced. Finally, a lower amplitude component can also result from the superposition of another component of opposite polarity in the latency range of the component of interest. In the present study it is difficult to ascertain the exact reason for the lower P3 amplitudes of alcoholic fathers and their sons. Since all subjects were given practice on the CPT until they correctly identified five consecutive matches, it is unlikely that they were misperceiving the target stimuli. In addition, there was not a significant difference in the error rates between the A + and N A - boys: Since single trials were not recorded (averages were computed on-line), it is not possible to rule out latency jitter as a cause of the reduced amplitude P3. However, trial-to-trial variability in responding to target stimuli may also be significant for understanding the nature of the atypical P3s of A + fathers and their sons. This is an empirical question awaiting further study. Visual inspection of the grand mean waveforms from the CPT targets (Fig. 3) shows that the difference between A + and control groups may not be restricted to P3. Particularly for the sons, the maximal difference appears in a negativity between the P2 and P3 peaks. This suggests that a type of processing needed for certain demanding tasks may result in scalp-recorded negativity that is larger for alcoholics and their sons, and that this negativity coincides more with the peak of P3 in adults, where P3 peaks at shorter latency. Inspection of the grand mean waveforms from the CPT (Fig. 2) may provide an additional clue to the underlying functional difference between groups. Note that the waveform for the target stimuli (solid line) at the Pz and Cz electrode locations for the A + boys is quite similar to the nontarget waveform (dotted line). A similar pattern is seen in the fathers. This would seem to indicate that the A + boys and their fathers are responding in a similar fashion to both classes of stimuli, whereas the other subjects were not. Even though the interaction between group and stimulus was not significant, there was a trend in the interaction for the sons P3 data ( p = 0 . 1 0 ) . Projesz and associates (25,27) report similar findings in alcoholic subjects, i.e., similar responses to both target and nontarget stimuli. Alcoholics and their sons may have difficulty differentiating between targets and nontargets in the use of some processing mechanism. The nonalcoholic controls who had a family history of alcoholism were included in the present study because nonalcoholic family history positive men have been shown to have reduced neuropsychological performance (28). We hypothesized that if familial alcoholism has a genetic component and P3 amplitude. reductions are one phenotypic manifestation, then perhaps some of these men and their sons would exhibit the same phenotype as the alcoholics, producing a group lying somewhere between the other two groups. Comparisons between NA + fathers and sons and N A - fathers and sons revealed no significant differ-
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e n c e s in either amplitude or latency o f P3 on either the C O L O R task or C P T . A l t h o u g h there were small S W differences between N A + and N A fathers, they went in opposite directions for the two tasks. While Fig. 3 s h o w s the C P T task did produce LPC amplitudes intermediate between the N A - and A + m e n , the differences between N A + and N A - were not significant. Because the N A + subjects are, on the average, less closely related to the alcoholic m e m b e r s of their families than the A + subjects, the N A + group is likely to include more subjects that did not inherit the g e n e s that put them at risk for alcoholism. Therefore. any physiological c o n s e q u e n c e s o f these g e n e s will be more difficult to d e m o n s t r a t e in the NA + group. T h e results o f this study support the hypothesis that P3 abnormalities can be used as one c o m p o n e n t of an atypical neurocognitive profile which can serve as a vulnerability m a r k e r for alcoholism, but only if a sufficient d e m a n d i n g and appropriate task is e m p l o y e d . Further research is needed to delineate the m i n i m u m requirements o f an appropriate task. However, it is important to assess the P3 variable in c o m b i n a t i o n with other m e a s u r e s for the s a m e reason that any single test of a neuropsychological batte~" has little diagnostic significance in isolation:
the defect can be produced by multiple etiologies. While a genetic vulnerability to alcoholism m a y be sufficient to produce reduced P3, it is clearly not a necessary condition, as P3 anaplitude can be reduced by physical factors such as the thickness of the skull, psychological factors such as the motivation of the subject, or by multiple chronic or acute disease states, such as schizophrenia or depression. W e are presently m a k i n g annual evaluations o f the boys of the present study in order to assess the onset and d e v e l o p m e n t o f drinking, drug use and other problem behaviors. In this way we hope to clarify the relative importance of lowered P3 amplitude, and the other c o m p o n e n t s o f the atypical neurocognitive profile reported in our earlier paper (33) as predictive m e a s u r e s with utility lbr early detection and c o u n s e l i n g in children at risk for d e v e l o p i n g alcoholism.
ACKNOWLEDGEMENTS The authors gratefully acknowledge the dedicated participation of the subject volunteers in the present stud.',,. This research was supported by the Seaver Institute. NIAAA grant AA-06960 and AA-08020, and the Pike Professorship of Alcohol Studies.
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